Synthesis of steroids



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United States Patent Otlice 3,050,535 Patented Aug. 21, 1962 3,050,535SYN'HESHS F STEROIDS Josef Fried, Princeton, NJ assignor to OlinMathieson Chemical Corporation, New York, N.Y., a corporation oiVirginia No Drawing. Filed .i'une 13, 1960, Ser. No. 36,464 Claims. (Cl.260-3914) wherein the 1,2 and/ or 6,7 positions are saturated or doublebonded; Q is hydrogen or methyl; R is hydrogen, lower alkyl (especiallymethyl) or halo (especially fluoro or chloro) in either the alpha orbeta position; R is R" or R"--O, R being a hydrocarbon radical of lessthan ten carbon atoms, such as lower alkyl (e.g., methyl, ethyl, butyland hexyl), monocyclic ar(lower alkyl) (e.g., benzyl, phenethyl, o, inand p-methylbenzyl and SI-phenylpropyl), and aryl (e.g., phenyl and o,m, and p-tolyl); and Z is hydrogen, halogen (especially chloro andfiuoro), hydroxy or the acyloxy radical of a hydrocarbon carboxylic acidof less than ten carbon atoms, such as an alkanoic acid especially thelower alkanoic acids (e.g., acetic acid, propionic acid, and hexanoicacid), a monocyclic aromatic carhoxylic acid e.g., benzoic acid, and o,m and p-toluic acids), a monocyclic lower aralkanoic acid (e.g.,phenylacetic acid and B-phenylpropionic acid), a lower alkenoic acid, alower cycloalkanoic acid, or a lower cycloalkenoic acid.

Among the compounds of this invention there may be phosphate esters of6a-fluoro-16a,l7a,21-trihydroxyprogesterone and 21-esters thereof (e.g.,the Ill-acetate);

(II) The 16a,17a-cyclophosphate and 16u,17a-cyclophosphonate esters of6-lower alkylated-l6a,l7oc-dihydroxyprogesterones, especially the16a,17a-cyclophosphate and l6ot,l7a-cyclophosphonate esters of6-rnethyl(or ethyl)46a,l7u-dihydroxyprogesterones, such as thel7a-cyclobenzylphosphate and 16a,17a-cyc1obenzylphosphonate esters of6a-methyl-16a,l7otdihydroxyprogresterone, the16a,17a-cyclomethylphosphate and 16oc,l7ot cyclomethylphosphonate estersof 6fi-1nethyl-l6ot,17ot-di hydroxyprogesterone, the16a,l7a-cyclophenylphosphate and l6cm,17ot-CYClOPhGIlYlPhOSPhOHEltGesters of 6B-ethy1- 16a,l7wdihydroxyprogesterone, the16a,l7a-cyclobenzylphosphate and l6a,l7a-cyclophenylphosphonate estersof 60 ethyl 1606,1706 dihydroxyprogesterone, the16u,17otcyclophenylphosphate and 16a,17u cyclophenylphosphonate estersof 6a-methyl-2l-fiuoro 16a,17a dihydroxyprogesterone, the16a,l7a-cyclornethylphosphate and 16a, l7a-cyclornethylphosphonateesters of' 6a methyl 16m, l7a-dihydroxy-l-dehydroprogesterone, thel6ot,l7a-cyclophenylphosphate and 1611,1711 -cyclophenylphosphonateesters of out-methyl 16a,l7a,21 trihydroxyprogesterone and Zl-estersthereof (e.g., the ZI-acetate), and the 16cc,

" 17a-cyclomethylphosphate and 16,17ot-cyclomethylphosphonate esters of6a,l65-dirnethyl 16ot,17a dihydroxyprogesterone;

(ill) The l6ct,17a-cyclophosphate and 16a,17oz-cyc1ophosphonate estersof 6-dehydro-16a,l7a-dihydroxyprogesterones, such as the16a,l7a-cyclobenzylphosphate and 16a,l7ot-cyclobenzylphosphonate estersof 6-dehydro-16a, l7oc-dihydroxyprogesterone, the1606,1706-CYC1OP11611Y1P11OS- phate and 16ot,170t cyclophenylphosphonateesters of A -pregnatriene-16u,l7a-diol-3,20-dione, the16a,17ucyclobenzylphosphate and 16a,l7a-cyclobenzylphosphonate esters of6-dehydro-16a,17a,21trihydroxyprogesterone and Zl-esters thereof (e.g.,the ZI-acetate) and the l6a,l7u-cyclosulfate, and16a,17oz-cyclomethylphosphate and 16a,l7ot-cyclomethylphosphonate estersof 6-dehydro- 16,8-methyl- 16a, 1 7a-dihydroxyprogesterone; and

(IV) The l6a,l7a-cyclophosphate and 16a,17a-cyclophosphonate esters of6-unsubstituted-l6a,l7ot-dihydroxyprogesterones, such as the16a,17oa-cyclomethylphosphate and l6a,17a-cyclomethylphosphonate estersof l6a,l7adihydroxyprogesterone, the 16u,l7ot-cyclophenylphosphonate and16cc,l7a-cyclophenylphosphate esters of 21-fluoro-16a,17a-dihydroxyprogesterone, the 16m,l7u-cyclophenylphosphateand 16a,17a-cyclophenylphosphonate esters of16a,17a-dihydroxy-l-dehydroprogesterone, the16m,17et-cyclobenzylphosphate and l6oc,l7ot-CYClOb6I1ZY1- phosphonateesters of 16a,17a,2l-trihydroxyprogesterone and 2l-esters thereof (e.g.the ZI-acetate), and the 16m, 17a-cyclo-o-tolylphosphate and16a,17a-cyclo-o-tolylphosphonate esters of -rnethy1-160:,l7oc-dihYdI'0XY- progesterone.

The compounds of this invention can be prepared by a process of thisinvention which comprises reacting a steroid of the general formula:

CHZZ

wherein the 1,2 and/ or the 6,7 positions are saturated or doublebonded; R and Q are as hereinbefore defined and Z is hydrogen, halogen(e.g. chloro or fiuoro) or an acyloxy radical of a hydrocarboncarboxylic acid of the group hereinbefore defined, with a phosphonyldichloride of the formula:

wherein R is as hereinbefore defined, in the presence of a hydrogenchloride acceptor, such as an organic nitrogen base (e.g., pyridine,collidine, triethanolamine and quinoline), and recovering the16,17-cyclic ester thus formed. The reaction is preferably carried outat a temperature below 0 C. by treating a solution or suspension of thesteroid in the basic medium with the phosphoryl dichloride and thenrecovering the product by conventional procedures.

The steroidal starting materials for preparation of the compounds ofthis invention are, generally, C-ring unsubstituted derivatives of16,17-dihydroxyprogesterones. Among the suitable steroidal startingmaterials there may be mentioned inter alia:

(I) 6-halogenated-l6a,17a-dihydroxyprogesterones, especially 6-fiuoroand 6-chloro-dihydroxyprogesterones,

. such as 6 x-fluoro-l6a,l7a-dihydroxyprogesterone, and

21-esters of 6a-fluoro-l6a,l7on2l-trihydroxyprogesterone (e.g. the21-acetate);

(II) 6-lower alkylated-16oc,l7ot dihydroprogesterones, especially6-rnethyl(or ethyl)46a,l7a-dihydroxyprogesterones, such as6oc-I1'16ihyl-160c,l7zx-dihj/d1OXYPIOg8St6fone,6a-ethyl-16a,17a-dihydroxyprogesterone, 6m-methyll 6u,l7x-dihydroxy-l-dehydroprogesterone, and 21-esters of6a-methy1-16a,170,2l-trihydroxyprogesterone (e.g., the 21-acetate); and

(III) 6-unsubstituted-l6a,17a dihydroxyprogesterones, such as16a,17a-dihydroxyprogesterone, 1606,1706-dlhY-droxy-l-dehydroprogesterone, 2l-esters of 16a,17a,21-trihydroxyprogesterone (e.g., the 21-acetate) and 16 3- methyl-1617ot-dihydroxyprogesterone.

Where a particular l-dehydro steroid is desired and only thecorresponding 1,2-saturated derivative is available, the latter can beconverted to the former by 1,2-

dehydrogenation with Bacterium cyclooxydans in accordance with themethod set out in Example 1 of US. Patent No. 2,822,318.

The -6-halo-16ot,.17a-dihydroxyprogesterones used herein are describedin copending application, Serial No. 7,521, filed February 9, 1960. The6-methyl-16a,17adihydroxyprogesterone starting materials used herein aredescribed in application Serial No. 830,467, filed July 30, 1959.

' The 21-acyloxy-16,17-esters of this invention can be prepared by thealternative process which comprises treating the16a,17a,21-trihydroxyprogesterone starting material with acetone andperchloric acid followed by treatment with an acid anhydridecorresponding to the acyloxy radical desired to yield thel6a,17a-acetonide-21-acylate which is treated with formic acid tohydrolyze the 16,17- ketal group. The 16a,17u,21-trihydroXy-2i-acylatederivative is converted to its 16,17-cyclic ester by the hereinbeforedescribed treatment with a phosphoryl dichloride.

The 21-halogenated esters of this invention can alternatively beprepared by treating the corresponding 16a,17a,2l-trihydroxyprogesteronewith acetone and perchloric acid to yield the corresponding16,17-acetonide and treating the latter with an organic sulfonyl halidesuch as mesyl chloride or tosyl chloride to form the 21-sulfonyloXy-16,17-acetonide derivative which is then treated with analkali metal halide such as lithium chloride, lithium bromide, sodiumiodide or potassium bifluoride to yield the corresponding ZI-chloride,bromide, iodide, or fluoride, respectively. The 21-halo-16,17-

acetonides are deacetonated by hydrolysis with an acid (e.g., formicacid) and then treated with a phosphoryl dichloride as hereinbeforedescribed, to yield the desired 16,17-esters of this invention.

The 6-dehydro-l6,17-esters of this invention may be prepared by reactingthe corresponding 6,7-saturated starting material with a6,7-dehydrogenating agent (e.g., chloranil in a mixture of ethyl acetateand acetic acid) and separating the 6-dehydro derivative thus formed.

The 16,8-methyl-16,17-esters of this invention are prepared byketalizing a l6-methyl-A -pregnadiene-3-ol-20- one with a lower alkyleneglycol in the presence of an acid catalyst (e.g. toluenesulfonic acid),treating the resulting 20-ethylene ketal derivative with an oxidizingagent such as aluminum tertiary butoxide in cyclohexanone to form thecorresponding A -3-one, which is then converted to16fl-methyl-16u,l7a-dihydroxyprogesterone 20-ethylene ketal by treatmentwith osmium tetroxide followed by a reducing agent such as hydrogensuifite. The dihydroxy compound is converted to its cyclic phosphate orphosphonate ester by a two step process involving either hydrolysis ofthe 20-ketal group with an acid (e.g., sulfuric acid) and thenesterification at the 16,:17- positions with a phosphoryl dichloride orfirst esterification at the 16,17-position with a phosphoryl dichlorideand then hydrolysis of the ketal radical with an acid (e.g., perchloricacid).

The 6fl-methyl and 6,8-halo cyclic esters of this invention are preparedby treating a 6fi-methylpregnane- 50L,l6o,17octli0l3,20-dl01'l (preparedas disclosed in my copending application Serial No. 830,467, filed July30, 1959) or the corresponding 6,6-halo-triol (described in the sameapplication) with a phosphoryl dichloride in an organic base ashereinbefore disclosed to simultaneously esterify the 16,17-position anddehydrate the 4,5a-position thereby yielding6fi-I1'16'E1'1Yl-160,i17oz-dlhYCllOXYP1'Og6S'LfiI- one-l6wl7a-cyclicester or the 6B-halo-16a,l7oz-dihydroxyprogesterone I16a,17oc-CYCliCester, respectively.

If a 21-acyloxy steroid is employed as the starting material and thecorresponding 21-hydroxy steroid is desired as the final product, the 21acyloxy- 16cc,17a dihydroxyprogesterone 160:,17m-CYCliC ester product ishydrolyzed as by treatment with an alkali metal carbonate (e.g.potassium carbonate) to yield the desired free 21-hydroxy final product.Alternatively, the ZI-acyloxy products of this invention may beconverted to the corresponding 11,8-hydroxy-2l-acyloxy-derivatives byknown methods [such as by subjecting the 2l-acyloxy ll-desoXy-startingmaterial to microbiological oxidation by the enzymes of Cunninghamellablakesleeana as disclosed in Steroids, Fieser, pg. 673 (1959)].

The compounds of this invention as represented by Formula I arephysiologically active substances which possess progestational andanti-uterotrophic activity and hence can be used in lieu of knownprogestational agents, such as progesterone, in the treatment ofdiseases and conditions such as habitual or threatened abortion,amenorrhea, metropathic hemorrhagica, dysmenorrhea, inadequate corpusluteum function and premenstrual tension, being formulated for suchadministration in the usual perorally or parenterally acceptableformulations.

The following examples illustrate, without limiting this invention (alltemperatures being in degrees centigrade):

EXAMPLE 1 1604,] 7a-Dihydroxyprogesterone 160L,170t-Cyclophenylphosphonate To a solution of 100 mg. of l6u,l7u-dihydroxyprogesterone in 3 ml. of anhydrous pyridine is added atl5 with stirring 0.2 ml. of phenylphosphonyl dichloride.

The reaction is allowed to proceed at 15 for /2 hour,

after which time Water and ice are added cautiously. The mixture istaken up in chloroform and water and the lay- 7 ers separated. Thechloroform layer is extracted with water, 1 N sulfuric acid, water,dilute sodium bicarbonate and again with Water, dried over sodiumsulfate and the solvent removed in vacuo. The resulting residue (about103 mg.) after recrystallization from acetone furnishes pure16a,17a-dihydroxyprogesterone 16u,17otphenylphosphonate having thefollowing properties: M.P. about 255; [a] +l48 (c., 1.08 in chlf.);

as}; 220 m (e=17,300), shoulder 224 m (e=l6,900) 238 m (e -16,800);A231? 5.81, 5.96, 6.18, 6.26 (phenyl), 7.92 (1 8.85 (POC), 9.65 (PO-C),10.02 (P-phenyl), 13.33, 13.91 and 1446p. (phenyl).

Anaylsis.Calcd for C27H33O5P (468.51): C, 69.20; H, 7.09; P, 6.61.Found: C, 69.02; H, 7.03; P, 6.65.

EXAMPLE 2 16:1,] 7a-Dihydr0xy-1-Dehydr0pr0gester0ne ]6ct,17ct-Cyclophenylphosphate To a solution of 100 mg. of16a,17a-dihydroxy-l-dehydroprogesterone (prepared by dehydrogenating16a,17otdihydroxyprogesterone with Bacterium cyclooxydans in accordancewith Example 1 of U.S. Patent No. 2,822,318) in 3 ml. of anhydrouspyridine is added at l5 with stirring 0.2 ml. of phenyl phosphoryldichloride. After one-half hour, ice water is added slowly and themixture is taken up in chloroform. The chloro form extract is washedwith Water, 1 N sulfuric acid, Water, dilute sodium bicarbonate andagain with Water, dried over sodium sulfate and the solvent removed invacuo. The resulting residue after recrystallization from acetone-hexanefurnishes 16a,17a-dihydroxy-1dehydroprogesterone 1611,17 a-cyclophenylphosphate.

EXAMPLE 3 1 6 0a,] 7a,2l -Trihydroxy progesterone 1 6 0a,] 7a-Cycl0-methylph osphate 21-Acetate To a solution of 100 mg. of16u,17a,21rtrihydroxyprogesterone 21-acetate (prepared by treating 100mg. of 16ahydroxycortexolone with acetone and 0.01 ml. of 70% perchloricacid to yield the 16,17-acetonide derivative of 16ot-hydroxycortexolonewhich is first transformed to its 21-acetate by treatment with pyridineand acetic anhydride and then to the desired 16a-hydroxycortexolone21-acetate by hydrolysis of the 16,17-ketal group with 60% aqueousformic acid) in 3 ml. of anhydrous pyridine is added at with stirring0.2 ml. of methylphosphoryl dichloride. The reaction is allowed toproceed at this temperature for /2 hour, after which time water and iceare added and the mixture is taken up in chloroform. The chloroformextract is washed with water, 1 N sulfuric acid, Water, dilute sodiumbicarbonate and again with water, dried over sodium sulfate and thesolvent removed in vacuo leaving the prouct16a,17u,2l-trihydroxyprogesterone 16a,17a-cyclo-methylphosphate21-acetate.

EXAMPLE 4 16/3-Methyl-1 6a,] 7u-Dihydroxyprogsterone 16 7a-Cyclophenylphosphonate (A) Preparation of A-16-methylpregnadiene-3{3-01- -one 20-ethylene ketal: A mixture of 3 g.of 73 -16- methylpregnadiene-3fl-ol-20-one, 9 ml. of ethylene glycol and112 ml. of benzene is heated at reflux with stirring with the aid of aDean-Stark separator. When 20 ml. of benzene has distilled, 186 mg. oftoluenesulfonic monohydrate is added to the mixture and the reaction isallowed to proceed with stirring for 16 hours at reflux temperature.After cooling, the mixture is neutralized by the addition of sodiumbicarbonate solution followedby the addition of water. The layers areseparated, the benzene extract Washed with Water, dried over sodiumsulfate and evaporated to dryness in vacuo. The crystal line residueafter recrystallization from acetone furnishes the pure ketal of thefollowing properties: M.P. about 168l69; 82 (0., 1.25 in chlf.);

and evaporated to dryness in vacuo.

Analysis.-Calcd for C H O (372.53): C, 77.34; H, 9.74. Found: C, 77.22;H, 9.40.

(B) Preparation of A -16-methylpregnadiene-3,20- dione-20-ethyleneketal: A solution of 2.5 g. of A -16- methylpregnadiene-lifl-ol-20-one20-ethylene ketal in a mixture of '90 ml. of xylene and 30 ml. offreshly distilled cyclohexanone is distilled until 5 ml. of distillatehave been collected. To this solution is added 2.5 g. of aluminumtertiary butoxide and the resulting solution is refluxed for 50 minutes.Water is added and after separation of the layers the aqueous phase isextracted thorough- 1y with chloroform. The combined xylene andchloroform extracts are dried over sodium sulfate and the solvents andthe cyclohexanone removed in high vacuum. The remaining residue is takenup in hexane and chilled, upon which crystallization occurs. Yield:about 1.69 g. The analytically pure material obtained afterrecrystallization from acetone, exhibits the following properties: M.P.about 175-177; +61 (0., 1.1 in chlf.);

r g- 240 mu (=15,700) my 5.99, 6.12 and 6.21

Analysis.Calc-d for C H O (370.51): C, 77.80;

H, 9.25. Found: C, 77.76; H,'9.38.

' (C) Preparation of 16B-methyl 16a,17m-dihydroxyprogesteroneZO-ethylene ketal: To a solution of 555 mg. of A46-methylpregnadiene-3,20-dione 20-ethylene ketal in 45 ml. of benzeneand 2.25 ml. of pyridine is added 438 mg. of osmium tetroxide. Thevessel containing the reaction mixture is stored in total darkness atroom temperature for 21 hours. ml. of dlioxane is then added and theresulting solution saturated with hydrogen sulfide for 7 minutes. Theosmium precipitate is centrifuged off and the clear solution added tochloroform and water. The organic layer is washed several times Withwater, dried over sodium sulfate and evaporated to dryness in vacuo.There remains a crystalline residue which after recrystallization fromacetone-hexane furnishes pure 16-methyl-16a,17a-dihydroxyprogesterone20- ethylene ketal of the following properties: M.P. about 186-187" andabout 172174 (polymorphic modifications); [a] .|74 (c., 1.38 in chlf.);+54 (0., 1.24 in methanol) A313; 240 mu (e=16,100); x53 1 2.99, 6.03 and6.23

Analysis.Calcd for C H O (404.53): C, 71.25; H, 8.97. Found: C, 70.88;H, 9.19.

(D) Preparation of 16,8-methyl-16a,17a-dihydroxyprogesterone16a,17a-cyclophenylphosphonate 20'-ethyl ene ketal: To a solution of 200mg. of 16/3-methyl-16a, 17asdihydroxyprogesterone 20-ethylene ketal in 6ml. of pyridine is added at 15 with stirring 0.4 ml. of phenylphosphonyl dichloride and the reaction is allowed to proceed at thattemperature for 30 minutes. Ice water is then added and the mixtureworked up as in Example 1 to give pure16,8-methyl-l6a,17a-dihydroxyprogesterone 16a,17a-cyclophenylphosphonate20-ethylene ketal.

(E) Preparation of l6B-methyl-l6a,17a-dihydroxyprogesterone16a,17ct-cyclophenylphosphonate: To a solution of mg. of16fl-methyl-16a,17a-dihydroxyprogesterone 16ml7a-cyclophenylphosphonate20-ethylene ketal in 12 ml. of methanol is added 1.04 ml. of 70%perchloric acid andthe mixture is stirred at room temperature for 16hours. Water is added and the solution is neutralized with sodiumbicarbonate. The bulk of the methanol is removed in vacuo and theresulting suspension extracted with chloroform. The chloroform extractis Washed with water, dried over sodium sulfate The residue aftercrystallization from methanol yields16,8-n1ethyl-16u;17adihydroxyprogesterone16a,17a-cyclophenylphosphonate.

(F) Alternative preparation of 16 3-methyl-16a,17a-dihydroxyprogesterone1611,170: cyclophenylphosphonate: A solution of 78 mg. of16fl-methyl-16a,17u-dihydroxyprogesterone ZO-ethylene ketal in 23 m1. ofmethanol and, 78 ml. of 8% sulfuric acid is heated under reflux for 45minutes. The mixture is cooled, neutralized with dilute sodiumbicarbonate and after removal of the bulk of the methanol in vacuoextracted with chloroform. The chloroform extract is washed with water,dried over sodium sulfate and evaporated to dryness in vacuo. Theresidual material after recrystallization from acetonehexane furnishespure l6B-methyl-16a,17a-dihydroxyprogesterone of the followingproperties: M.P. about 2S8261; [a] +44- (c., .39 in chlf.);

xggg- 239 m, $17,200 x 1 2.95, 6.05 and 6.21

Analysis.Calcd for C H O (360.48): C, 73.30; H, 8.95. Found: C, 73.32;H, 8.92.

Reaction of the 165-methyl-16a,l7a-dihydroxyproges terone withphenylphosphonyl dichloride in pyridine at l5 as described in part Dfurnishes the 16,17-cyclophenylphosphonate identical with the product otained in part E.

EXAMPLE 5 21-Flu0ro-1 6 0a,] 7oc-Dihydr0xypr0gestel'0ne 1 6 a,] 7 a- Cyclobenzylphosphonate 16a,170:,21-trihydroxyprogesterone is treated withacetone and perchloric acid to form 16a,17oz,2l-trihydroxyprogesteronell6e,l7ot-acetonide, which is then treated with mesyl chloride inpyridine under anhydrous conditions at a temperature of 0. After twohours, water is added and the precipitated 2l-mesylate is removed byfiltration, washed thoroughly, dried in vacuo and recrystallized fromacetone-hexane. The crystalline mesylate is dissolved in ethylene glycoland treated with potassium bifluoride at reflux temperature for fortyhours after which the reaction mixture is diluted with Water and thecrystals filtered off, dried in vacuo and then recrystallized fromacetone-hexane to yield the product21-fluoro-16a,l7a-dihydroxyprogesterone 1600,17- acetonide.

The 16,17-acetonide is deacetonated by treatment with 60% aqueous formicacid at 40 to yield 2l-fluoro- 16a,l7a-dihydroxyprogesterone which isconverted by treatment with benzylphosphonyl dichloride in accordancewith the procedure of Example 1 to the product 21fluoro-16a,17u-dihydroxyprogesterone 16oc,l7rx-CYC10- benzylphosphonate.

Similarly, except for the introduction of the phenylphosphonyl groupinto the corresponding 21-chloro, 21-bromo and -21-iodo derivatives(prepared by treating the 21-mesylate with lithium chloride, lithiumbromide and sodium iodide respectively) there are obtained21-chloro-16a,17ot-dihydroxyprogesterone 160:,17oc-CYC10-phenylphosphonate, 21-b1'OlIlO-160C,170t-dihYdl'OXYPX'OgfiS- terone116a,17a-cyclophenylphosphonate, and 21-iodo- 16u,17adihydroxyprogesterones 16at,17-u cyclophenylphosphonate, respectively.

EXAMPLE 6 1 6 04,1 7a-Dihydr0xy progesterone 1 6 04,] 7a-Cyclophenylphosphate To a solution of 200 mg. of16a,17a-dihydroxyprogesterone in 6 ml. of pyridine is added at 15, 04ml. of phenylphosphonyl dichloride. The reaction is allowed to proceedat 15 for 30 minutes after which time ice water is added and the mixtureis extracted with chlor0- form. The chloroform extract is washed withwater,

1 6 ,B-M ethyl-1 6 oz,] 7m-Dihydr0xyprogester0ne 1611,1711-Cyclophenylphosphate Following the procedure of Example 6, phenylphos-The crystalline residue,..

Q phoryl dichloride is added to 16[3-methyl-16a,17a-di-'hydroxyprogesterone in pyridine at -15. The reaction is allowed toproceed at l5 for 30 minutes after which time ice water is added and themixture is extracted with chloroform. The chloroform extract is washedwith water, 1 N sulfuric acid, water, dilute sodium bicarbonate andagain with Water, dried over sodium sulfate and the solvent evaporatedin vacuo leaving a crystalline residue which is recrystallized fromacetone-hexane to yield the product 16 3 methyl 16u,17adihydroxyprogesterone 16a,17ct-cyclophcnylphosphate.

EXAMPLE 8 6 oc-F luoro-l 6 00,1 7a-Dihydr0xypr0gester0ne 6 oz,] 7a-Cyclophenylphosphonate To a solution of mg. of6ot-fluoro-l6u,17ot-dihydroxyprogesterone in 3 ml. of pyrid'ine'is addedwith stirring at l5 0.2 ml. of phenylphosphonyl dichloride. The reactionis allowed to proceed at 15 for 1.2 hours, after which ice is added andthe mixture taken up in chloroform. After separation of the layers, thechloroform extract is washed with water, 1 N sulfuric acid, Water,dilute sodium bicarbonate and again with Water, and dried over sodiumsulfate. Evaporation of the chloroform solution in vacuo leaves as aresidue, the product 60c fiuoro 1606,1711 dihydroxyprogesterone 16a, 17a-cyclophenylphosphonate.

EXAMPLE 9 6a-Clzloro-1 60:,1 7tx-Dihydroxyprogesterone 1 6 0a,] 70:-Cyclom ethy phosphate Following the procedure of Example 8 an equivalentamount of 6u-chloro-16or,l7a-dihydroxyprogesterone (prepared by treating16a,17ot-epoxyprogesterone in dioxane with ethyl orthoformate in ethanoland sulfuric acid to form 3-ethoXy-l6m,l7a-epoxy-A -pregnadiene- ZO-onewhich is treated in a dioxane solution with N-chlorosuccinimide and asodium acetate-acetic acid buffer, followed by dilution with water. Theresulting 6,8-ch1oro-l6a,17a-epoxyprogesterone dissolved in acetic acid,is treated with 33% HBr to yield 6or-chloro-16/3 bromo-A'-pregnene-l7u-ol-3,20-dione. The latter is converted to its l7ot-acetoxyderivative by treatment with acetic anhydride in 70% perchloric acid andthis product is treated with sodium acetate in acetic acid to yield606-011101'0 160;,170: dihydroxyprogesterone 16a-acetate, which isfinally treated with methanolic potassium car bonate to yield thedesired 6ot-Cl1lOIO-16a,17oc-dihYdl'OXY- progesterone) is treated withmethylphosphoryl dichloride to yield the product6oc-Chl0I'O-16ot,17ot-dihYdI'0XY- progesterone16a,17a-cyclomethylphosphate.

EXAMPLE 10 6uc-FlldOr0-1 6a,] 7a-Dihydi'0xy-1-Dehydr0pr0gester0ne 1606,]7wCyclophenylphosphonate 6a fluoro 1606,1742 dihydroxyprogesterone16,17- cyclophenylphosphonate is microbiologically 1,2-dehydrogenated inaccordance with the procedure of Example 1 of US. Patent No. 2,822,318to yield the product 60:- fiuoro 16u,l7or dihydroxy ldehydroprogesterone 16a,17a-cyclophenylphosphonate.

EXAMPLE ll 6 fi-Fluoro-J 6 u,1 7 a-DihydroxyprogesteroneJ6a,Z7a-Cyclophenylphosphonate (A) Preparation of6l3-fluoroprcgnane-5a,l6cx,l7atriol-3,20-dione 16a,l7e-cyclophenylphosphonate: To a solution of mg. of6,6-fluoropregnane-5u,16a,17rxtriol-3,20-dione (prepared as described inSerial No. 859,840 filed December 16, 1959) in 5 ml. of dry pyridine isadded l5 0.3 ml. of phenylphosphonyl dichloride. After 30 minutes at l5ice water is added and the mixture extracted with chloroform. Thechloroform extract is worked up as described in Example 1 to give6fi-fiuoropregnane 5a,16ot,17a triol 3,20 dione 16a, 17u-cyclophenylphosphon at:

(B) Preparation of 6e-iluoro-16a,17u-dihydroxyprogesterone16a,17a-cyclophenylphosphonate: To a solution of 150 mg. of6;8-fiuoropregnane-5u,l6a,17u-triol-3,20- dione16a,17a-cyclophenylphosphonate in 6 ml. of dry pyridine is added at 0.6ml. of thionyl chloride. The mixture is allowed to stand at 0 for 30minutes, after which time ice is added and the mixture extracted withchloroform. The chloroform extract is washed with 2 N hydrochloric acid,Water, dilute sodium bicarbonate and again with Water, dried over sodiumsulfate and evapo rated to dryness in vacuo. The resulting residue isdis solved in a mixture of 5 ml. of chloroform and 25 ml. of benzene andpoured through a column of 1 g. of neutral alumina. The efiluentfurnishes crystalline ma terial which after recrystallization fromacetone-hexane represents pure 6,8-fluoro-16ot,17a-dihydroxyprogesterone16a,17u-cyclophenylphosphonate.

EXAMPLE 12 6-Dehydr0-1 6 0a,] 7ot-Dihydroxyprogesterone 1 6 0a,] 7a-Cyclopheny lph osphonate A solution of 250 mg. of16a,17a-dihydroxyprogesterone 16a,17a-cyclophenylphosphonate and 500 mg.of recrystallized chloranil is heated under reflux in a mixture of 10ml. of ethyl acetate and 2 ml. of glacial acetic acid for 20 hours. Themixture is cooled, poured into Water and the layers separated. Afteradditional extraction of the aqueous layer With ethyl acetate, the ethylacetate extract is Washed with 1 N sodium hydroxide solution until theaqueous layer becomes colorless. The ethyl acetate extract is washedwith water, dried over sodium sulfate and evaporated. to dryness invacuo. The crude residue is dissolved in benzene and chromatographed on6 g. of neutral alumina. Elution of the column With 200 ml. of benzenecontaining 5% chloroform, furnishes the crystalline phenylphosphonateester which is analytically pure after recrystallization fromacetone-hexane.

EXAMPLE 13 A -Pregnatriene-I 6a,] 7a-di0l-3,20-Dione 1 6a,] 7u-Cyclopheny lphosphonate The product of Example 12 is microbiologicallydehydrogenated with Bacterium cyclooxydans in accordance with theprocedure of Example 1 of US. Patent No. 2,822,318 to yield the productA -pregnatriene-16a, 17x-diol-3,20-dione16a,17ot-cyclophenylphosphonate.

EXAMPLE l4 1 6 0a,] 711,21 -Trihydr0xy-6Dehydroprogesterone 1 6a,]7u-Cycl0methylph0sphate 21 -Acetate The product of Example 3,16u,l7a,21-1;1ihydlOXY- progesterone 16a,17u-cyclomethylphosphateZI-acetate, is treated with chloranil in ethyl acetate and acetic acidin accordance with the procedure of Example 12 thereby yielding theproduct 16a,170:,21-trihydroxy-6-dehydroprogesterone,16a,17a-cyclomethylphosphate.

EXAMPLE l5 6-Methyl-6-Dehya'r0-16 1 7a-Dihydroxyprogesterone 160a,]7a-Cycloplzenylphosphonate A solution of 145 mg. of6OL-Hlethyl-160,17OL-dlhYdIOX- yprogesterone l6a,l7acyclophenylphosphonate (prepared in Example 18) and 300 mg. of chloranilin a mixture of 7.5 ml. of ethyl acetate and 1.5 ml. of acetic acid isheated under reflux for 42 hours. The reaction mixture is Worked up asdescribed in Example 12. Evaporation of the ethyl acetate extract invacuo yields a residue 10 which is dissolved in 5 ml. of benzene andchromatographed on 4.5 g. of neutral alumina. Elution with benzenefurnishes crystalline material which is recrystallized fromacetone-hexane.

EXAMPLE 16 6 fiM ethyl-1 6 04,1 7a-Dihydroxypr0gester0ne 1 6 0a,] 7ot-Cyclophenylphospha'te To a solution of 190 mg. of6fi-methylpregnane-5u, 16u,17a-triol-3,20-dione (prepared as describedin my copending application Serial No. 764,495, filed October 1, 1958)in 5 ml. of dry pyridine is added at -15 0.5 ml. of phenylphosphoryldichloride. After 30 minutes at 15, ice water is added and the mixtureworked up as in Example 2 to give pure6B-methyl-16a,17u-dihydroxyprogesterone 16a,17ot-cyclophenylphosphate.

EXAMPLE l7 6,8-Methyl-16a,1 7n-dihydroxy-l -Dehydropr0gesterone 16:1,]7a-Cycl0pheny[phosphate Treatment of the product of Example 16 inaccordance with the microbiological dehydrogenation procedure outlinedin Example 1 of US. Patent No. 2,822,318, furnishes the product 68-methyl-16u,17m-dihydroxy-1-dehydroprogesterone16a,17u-cyclophenylphosphate.

EXAMPLE 18 6 a-M eth yl 1 6 0a,] 7a-D ih yd Foxy progesterone 1 6 a,] 7u-Cyclophenylphosphonate (A) Preparation of6tx-methyl-1'6a,17m-dihydroxyprogesterone: To a solution of 3.69 g. of6cx-methyl-l6-dehydroprogesterone dissolved in 30 ml. of benzene and 3.6ml. of dry pyridine is added in the dark, dropwise, With stirring over aperiod of 2 hours, a solution of 3 g. of osmium tetroxide in 45 ml. ofbenzene. The resulting mixture is stirred in the dark for an additional3% hours, after which 75 ml. of benzene, 138 ml. of methanol, 204 ml. ofWater, 21.3 g. of sodium sulfite, and 21.3 g. of potassium bicarbonateis added and the mixture shaken for 18 hours. 250 ml. of chloroform isthen added and the resulting suspension shaken for an additional /2hour, filtered and the precipitate washed 3 times with ml. portions ofhot chloroform. After separation of the layers, the organic layer iswashed 3 times with Water, dried over sodium sulfate and the solventsremoved in vacuo. The resulting residue (about 4 g.) on crystallizationfrom acetone affords about 3.72 g. of 6a. methyl l6o,l7ocdihydroxyprogesterone, Ml. about 220226 C. After recrystallization fromacetone the pure glycol is obtained with the following properties: M.P.about 224-226 C.; [a] +68 (o, .99 in chlf.);

kg??? 2.95, 5.90, 6.02, 6.25 1; M13; 240 m,u(e=16,500)

Analysis.-Calcd for C H O (360): C, 73.30; H, 8.95. Found: C, 73.44; H,8.98.

(B) Preparation of 6ot-methyl-16a,l7m-dihydroxyprogesterone16a,17oc-cyclophenylphosphonate:' Soc-methyl-16a,17a-dihydroxyprogesterone (100 mg.) is treated with phenylphosphonyldichloride in pyridine exactly as described in Example 1 to yield theproduct 6a-methyl-16a, 17a-dihydroxyprogesterone16a,17a-cyc1ophenylphosphonate.

EXAMPLE 19 16a,1 7 (x,2 1 -Trihydroxy progesterone I 6 0a,] 70:-Cyclomethyl phosphate The product of Example 3 is treated With anaqueous solution of potassium carbonate at room temperature. Separationof the precipitate from the reaction mixture yields the product16a,17a,2l-trihydroxyprogesterone 16a,17a-cyclomethylphosphate.

This invention may be variously otherwise embodied within the scope ofthe appended claims.

1 1 What is claimed is: 1. A compound represented by the followinggeneral wherein the 1,2 and 6,7 positions are connected by a linkageselected from the group consisting of a single and a double bond; Q isselected from the group consisting of hydrogen and methyl; R is selectedfrom the group consisting of hydrogen, lower alkyl, fluoro and chloro; Ris a radical selected from the group consisting of R" and R"--O, R beinga hydrocarbon radical of less than ten carbon atoms; and Z is a memberselected from the group consisting of hydrogen, halogen, hydroxy, andthe acyloxy radical of a hydrocarbon carboxylic acid of less than tencarbon atoms.

2. 16a,17a-dihydroxyprogesterone 1600,170c-CYCPh61'1- ylphosphonate.

3. 6a fluoro l6ot,l7u dihydroxyprogesterone 16oz,17a-cyclophenylphosphonate.

4. 21 fluoro 16oc,17a dihydroxyprogesterone 16cc,l7a-cyclobenzylphosphonate.

5. A process for the preparation of the compounds ofclaim 1 whichcomprises treating a compound of the formula wherein the 1,2 and6,7-positions are connected by a linkage selected from the groupconsisting of a single and a double bond; Q is a member selected fromthe group consisting of hydrogen and methyl; R is a member selected fromthe group consisting of hydrogen, lower alkyl fluoro and chloro; and Zis a member selected from the group consisting of hydrogen, halogen, andthe acyloxy radical of a hydrocarbon carboxylic acid of less than tencarbon atoms, with a phosphoryl dichloride of the formula wherein R isselected from the group consisting of R" and R"-O-, R being ahydrocarbon radical of less than ten carbon atoms, in the presence of anorganic nitrogen base, and recovering the product thus formed.

No references cited.

an-wort,

1. A COMPOUND REPRESENTED BY THE FOLLOWING GENERAL FORMULA: